1. Field of the Invention
The present invention relates to a PTD-UQCRB fusion polypeptide, and a pharmaceutical composition for preventing and treating an ischemic disease, containing the same.
2. Description of the Related Art
Ischemia means a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism. Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue. It also means local anemia in a given part of a body sometimes resulting from congestion. In case of chronic ischemic heart diseases in which is one of representative ischemic diseases, myocardium is affected by abnormality of coronary circulation system and unsupplied sufficient amounts of oxygen and nutrients to accompany symptoms such as chest pain, dyspnea caused by heart failure, weakness and fainting. There has been a drastic increase in nowadays. In addition, insufficient blood supply to hair root and hair follicle prevents the formation of hair root and hair follicle such that hair loss or leukoplakia may be induced. In addition to this, blood supply interruption due to ischemia causes various ischemic diseases such as ischemic heart failure, ischemic enteritis, ischemic eye disease and ischemic limb disease. Therefore, there are attempts to treat ischemic disease by inducing angiogenesis.
VEGF (vascular Endothelial Growth Factor) is the endothelial cell-specific mitosis catalyst. VEGF is a glycoprotein with homodimer structure and exists in four different isoforms in human. VEGF-121 and 165 is a secretion protein. VEGF-189 and 206 act as growth factor by binding to heparin including proteoglycan in the cell surface or extracellular matrix. Representative receptors binding to VEGF are Flt-1 (Fml-like tyrosine kinase-1) and KDR (kinase domain-containing receptor). They are all expressed in endothelial cells, Flt-1 is mainly involved in cell migration and interaction between cells and KDR is involved in cell proliferation and survival.
Angiogenesis such as endothelial cell proliferation and migration, formation of capillaries is caused through signal transduction by binding of VEGF and its receptor and that is essential for regeneration of the wound as well as development and differentiation of organs during embryogenesis.
The fact that VEGF induce angiogenesis is well-known to those skilled in the art, and clearly supported by various literatures (Bruce I. et al, VEGF and Tumor Angiogenesis, Einstein Quart. J. Biol. and Med. 18:59-66(2001); Oettgen P, The role of ets factors in tumor angiogenesis, J Oncol., 2010:767384. Epub 2010 May 4; Berse B. et al, Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors, Mol Biol Cell., 3(2):211-20(1992)). Therefore, the direct injection of VEGF (Vascular Endothelial Growth Factor) induces angiogenesis such that ischemic disease may be treated.
However, since administration of VEGF only cannot effectively induce all the steps of angiogenesis including disruption of basement membrane, and proliferation, migration and differentiation of epithelial cells, angiogenesis occurs less organized than the natural angiogenesis. As hypoxia is known to induce angiogenesis in nature, the regulators to hypoxia may stimulate generation of one or more angiogenic factors simultaneously, thereby being expected to induce angiogenesis in a more organized and healthier manner than induction of each individual factor.
On the other hand, ubiquinol-cytochrome c reductase binding protein (UQCRB), one of the subunits of mitochondrial Complex III, is a target protein of terpestacin which inhibits angiogenesis. Particularly, it is encoded in the nucleus2 and plays a crucial role in the maintenance and assembly of Complex III structure3. Moreover, UQCRB is overexpressed in liver and stomach cancer cells and related to several diseases such as hypoglycemia, lactic acidosis, and myopathy4.
Many reports demonstrated that the mitochondrial respiratory chain Complex III plays as a crucial modulator in hypoxia-induced angiogenesis through reactive oxygen species (ROS) production and cellular oxygen sensing5-8. During hypoxia, ROS generated at mitochondrial Complex III stabilize hypoxia-inducible factor 1-α (HIF-1α) protein9, a master regulator of angiogenesis (FIG. 1). Hypoxia inducible factor (HIF) has been focused for its critical role in cell survival under hypoxic conditions and in the initiation of angiogenesis10-11. While HIF consist of HIF-1α and HIF-1β heterodimeric complex12, HIF-1α protein, in particular, is responsible for initiating expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF)13-14.
Throughout this application, several patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications is incorporated into this application in order to more fully describe this invention and the state of the art to which this invention pertains.